Osteoarthritis
ORIGINAL ARTICLE
Coronary heart disease is associated with a worse clinical outcome of hand osteoarthritis: a cross-sectional and longitudinal study Alice Courties,1 Jérémie Sellam,1 Emmanuel Maheu,1,2 Christian Cadet,2 Yoann Barthe,3 Fabrice Carrat,3 Francis Berenbaum1 To cite: Courties A, Sellam J, Maheu E, et al. Coronary heart disease is associated with a worse clinical outcome of hand osteoarthritis: a cross-sectional and longitudinal study. RMD Open 2017;3:e000344. doi:10.1136/rmdopen-2016000344 ▸ Prepublication history and additional material is available online. To view these files please visit the journal (http://dx.doi.org/10.1136/ rmdopen-2016-000344). Received 3 August 2016 Revised 8 December 2016 Accepted 9 December 2016
1
Rheumatology Department, Saint-Antoine Hospital, Inserm UMR S_938, UPMC Univ Paris 06, Assistance Publique–Hôpitaux de Paris (AP-HP), DHU i2B, Paris, France 2 Department of Rheumatology, Private Office, Paris, France 3 Public Health Department, Saint-Antoine Hospital, Inserm UMRS_1136, UPMC Univ Paris 06, AP-HP, Paris, France Correspondence to Professor Francis Berenbaum; [email protected]
ABSTRACT Objective: To determine whether cardiometabolic factors are associated with hand osteoarthritis (HOA) symptoms, radiographic severity and progression in a post hoc analysis of the phase III Strontium ranelate Efficacy in Knee OsteoarthrItis triAl (SEKOIA) trial, designed to determine the effect of strontium ranelate on knee osteoarthritis (OA). Methods: Among the 1683 patients randomised in the SEKOIA study, 869 with radiographic HOA at baseline (rHOA≥2 joints with Kellgren-Lawrence grade ≥2) were included in a cross-sectional analysis. For longitudinal study, we included only the 307 patients with rHOA at baseline from the placebo group. We evaluated whether baseline symptomatic HOA, radiographic severity and clinical and rHOA progression were associated with coronary heart disease and/or metabolic diseases (obesity, diabetes and hypertension, dyslipidaemia) by multivariate regression analysis. Results: At baseline, 869 patients (72% women) were included in the cross-sectional analysis; 26% were symptomatic. On multivariate analysis, symptomatic HOA was associated with coronary heart disease (OR 3.59, 95% CI (1.78 to 7.26)) but not metabolic diseases. After a mean follow-up of 2.6 years, for the 307 participants in the placebo group, on multivariate analysis, worse clinical HOA outcome was associated with coronary heart disease (OR 2.91, 95% CI (1.02 to 8.26)). The slow radiographic progression did not allow for revealing any associated factors. Conclusions: Symptomatic HOA and worse HOA clinical course are associated with coronary heart disease. These results strengthen the systemic component of HOA and the association between OA pain and cardiac events. Trial registration number: ISRCTN41323372.
INTRODUCTION Hand osteoarthritis (HOA) is a heterogeneous disorder because of its multiple risk
Key messages What is already known about this subject? ▸ Hand osteoarthritis (OA) diagnosis has been previously associated with atherosclerosis or cardiac events.
What does this study add? ▸ In a cohort of generalised OA, coronary heart disease was associated with hand OA symptoms but also worse clinical outcome, after a mean follow-up of 2.6 years.
How might this impact on clinical practice? ▸ This study strengthens the association between hand OA and cardiovascular diseases and supports that evaluating cardiometabolic comorbidities in OA participants may be useful.
factors such as inheritance, ageing, gender and obesity.1–3 In addition, HOA has been associated, although not always, with metabolic disorders (ie, diabetes, hypertension or dyslipidaemia), delineating the metabolic OA phenotype.4 5 Furthermore, cardiovascular disease (CVD) and mortality are more frequent in people with OA than without OA.6–9 A recent meta-analysis reported higher risk of CVD, especially heart failure and ischaemic heart disease, with OA than without OA but with a high heterogeneity in the design of the studies included.9 The relationship between CVD and OA has been attributed to disability, preventing people from exercising, therefore with increased cardiovascular risk. However, some studies have suggested a direct relationship between CVD and osteoarthritis (OA), independent of increased body weight and physical activity, which suggests a systemic association via a common
Courties A, et al. RMD Open 2017;3:e000344. doi:10.1136/rmdopen-2016-000344
1
RMD Open low-grade inflammation state. Indeed, HOA, which does not affect physical activity, has been independently associated with atherosclerosis or cardiac events.10 11 However, most of these studies compared CVD and metabolic disease outcomes between patients with and without HOA but did not evaluate their association with HOA symptoms or severity, which may be more representative of systemic inflammation. To better understand the association between metabolic diseases, CVD and OA, we investigated an association of cardiometabolic diseases with symptomatic HOA, radiographic severity and/or progression of HOA in a post hoc study of data from the Strontium ranelate Efficacy in Knee OsteoarthrItis triAl (SEKOIA; ISRCTN41323372), which carefully assessed HOA. PATIENTS AND METHODS Study design and patient population of SEKOIA SEKOIA is a randomised phase III, multicentre, placebocontrolled study evaluating the structural effect of strontium ranelate in knee OA. The design of this study has been previously described.12 Briefly, 1683 Caucasian patients ≥50 years old with symptomatic and primary knee OA fulfilling the American College of Rheumatology criteria with Kellgren-Lawrence (KL) knee grade 2 or 3 and minimum joint space 2.5–5 mm were randomised between April 2006 and March 2008. There were three treatment groups: strontium ranelate 1 g/day, strontium ranelate 2 g/day and placebo. The randomisation was stratified on centre and gender. Analgesics and non-steroidal anti-inflammatory drugs were permitted if stopped at least five half-lives before each visit to allow for proper symptom assessment. Patients were followed annually for 3 years, with the last visit on February 2011. The results of the main study have been previously reported.13 The study conformed to the principles of the Declaration of Helsinki; it was approved by the Ethics Committee or Institutional Review Board of every site. All patients provided written informed consent before randomisation. The trial is registered (ISRCTN41323372). Population of the ancillary study All patients with radiographic HOA (rHOA) defined as a KL score ≥2 for at least two joints at baseline were included in the cross-sectional analysis. For the longitudinal analysis, to avoid any treatment bias, we excluded patients from the treatment group and included only patients with rHOA from the placebo group at baseline. HOA evaluation For this post hoc ancillary study, bilateral anteroposterior hand radiographs taken at baseline and at the end of follow-up were scored with blinding to treatment group and in chronological order. Two expert readers 2
(EM and CC) scored half of the radiographs each, independently, by using the KL hand score (grade 0–4) for the following joints: proximal interphalangeals (PIPs 2–5), first interphalangeal (IP-1), distal interphalangeals (DIPs 2–5), metacarpophalangeals (MCPs 1–5), first carpometacarpal and scaphotrapezial. The KL hand score ranged from 0 to 128 (128 being the worst).14 Presence of erosive joints was determined by using the phase E (erosive phase) or R (remodelling phase) of the Verbruggen anatomical scoring system to analyse PIPs 2–5, IP-1, DIPs 2–5 and MCPs 1–5.15 Intrareader and inter-reader reproducibility were excellent, with intraclass correlation coefficient >0.8 for inter-reader reproducibility and >0.9 for intrareader reproducibility. Clinical evaluation of pain and disability due to HOA was assessed by the AUStralian/CANadian (AUSCAN) pain score,16 stiffness and function scores and total AUSCAN score as well as the Functional Index for HOA (FIHOA).17 For the AUSCAN, each of the three subscale scores was corrected to 100, for a range from 0 to 300 for the total score. Presence of pain was assessed by the question ‘Did you have pain in your hands during the past 48 hours?’, with a binary answer (yes/no). Definition of symptomatic HOA and clinical progression In the cross-sectional analysis, symptomatic HOA was defined by a FIHOA score ≥5 and hand pain in the past 48 hours (FIHOA≥5+presence of HOA pain). The FIHOA≥5 threshold was used because it discriminates between symptomatic and non-symptomatic HOA.18 In the longitudinal analysis, clinical progression was defined by deterioration in FIHOA score between baseline and the end of follow-up (FIHOA final minus FIHOA initial >0). The secondary clinical outcomes were AUSCAN pain score, used as a continuous variable, to determine baseline clinical symptom intensity and AUSCAN pain deterioration for clinical symptom changes. Definition of radiographic severity and radiographic progression We defined radiographic severity by using the KL hand score as a continuous variable. Radiographic progression was defined by a change in KL total score over each reader’s smallest detectable difference (SDD). The secondary structural radiographic outcomes were presence of at least one erosive joint on both hands based on the Verbruggen score ( phase E or R) and the occurrence of a new erosive joint in the cross-sectional and longitudinal analysis, respectively. Collected clinical data At baseline, the following demographic variables were collected from medical files, self-reported data and patient medications by SEKOIA study investigators without information on delay between the disease and the randomisation: age, gender, body mass index (BMI), Courties A, et al. RMD Open 2017;3:e000344. doi:10.1136/rmdopen-2016-000344
Osteoarthritis menopause status, alcohol consumption and tobacco use and comorbidities such as diabetes mellitus, hypertension, dyslipidaemia, depression, coronary heart disease (defined as acute myocardial infarction, angina pectoris, arteriosclerosis coronary artery, coronary artery disease/insufficiency/occlusion/stenosis/thrombosis, coronary heart disease, myocardial infarction and myocardial ischaemia), stroke and lower limb arteritis. Obesity was defined as BMI≥30 kg/m2. Statistical analysis Data were analysed by using SAS V.9.3 (SAS Institute, Cary, North Carolina, USA). Continuous variables are described as mean±SD or median (quartile 1–3) and categorical variables as frequencies and percentages. Comparison of cross-sectional and longitudinal data involved Fisher’s exact and Wilcoxon tests. In the crosssectional analysis, we used unadjusted logistic regression to analyse the following factors associated with symptomatic HOA (FIHOA score ≥5+pain): age, sex, menopause, obesity, history of diabetes, hypertension, dyslipidaemia, coronary heart disease (as described previously), depression, stroke, alcohol consumption, tobacco use, and rHOA and knee OA features. Linear regression was used to assess associations with AUSCAN pain and KL hand score, and logistic regression was used to assess an association with presence of at least one erosive joint. All factors associated on univariate analysis at p
ORIGINAL ARTICLE
Coronary heart disease is associated with a worse clinical outcome of hand osteoarthritis: a cross-sectional and longitudinal study Alice Courties,1 Jérémie Sellam,1 Emmanuel Maheu,1,2 Christian Cadet,2 Yoann Barthe,3 Fabrice Carrat,3 Francis Berenbaum1 To cite: Courties A, Sellam J, Maheu E, et al. Coronary heart disease is associated with a worse clinical outcome of hand osteoarthritis: a cross-sectional and longitudinal study. RMD Open 2017;3:e000344. doi:10.1136/rmdopen-2016000344 ▸ Prepublication history and additional material is available online. To view these files please visit the journal (http://dx.doi.org/10.1136/ rmdopen-2016-000344). Received 3 August 2016 Revised 8 December 2016 Accepted 9 December 2016
1
Rheumatology Department, Saint-Antoine Hospital, Inserm UMR S_938, UPMC Univ Paris 06, Assistance Publique–Hôpitaux de Paris (AP-HP), DHU i2B, Paris, France 2 Department of Rheumatology, Private Office, Paris, France 3 Public Health Department, Saint-Antoine Hospital, Inserm UMRS_1136, UPMC Univ Paris 06, AP-HP, Paris, France Correspondence to Professor Francis Berenbaum; [email protected]
ABSTRACT Objective: To determine whether cardiometabolic factors are associated with hand osteoarthritis (HOA) symptoms, radiographic severity and progression in a post hoc analysis of the phase III Strontium ranelate Efficacy in Knee OsteoarthrItis triAl (SEKOIA) trial, designed to determine the effect of strontium ranelate on knee osteoarthritis (OA). Methods: Among the 1683 patients randomised in the SEKOIA study, 869 with radiographic HOA at baseline (rHOA≥2 joints with Kellgren-Lawrence grade ≥2) were included in a cross-sectional analysis. For longitudinal study, we included only the 307 patients with rHOA at baseline from the placebo group. We evaluated whether baseline symptomatic HOA, radiographic severity and clinical and rHOA progression were associated with coronary heart disease and/or metabolic diseases (obesity, diabetes and hypertension, dyslipidaemia) by multivariate regression analysis. Results: At baseline, 869 patients (72% women) were included in the cross-sectional analysis; 26% were symptomatic. On multivariate analysis, symptomatic HOA was associated with coronary heart disease (OR 3.59, 95% CI (1.78 to 7.26)) but not metabolic diseases. After a mean follow-up of 2.6 years, for the 307 participants in the placebo group, on multivariate analysis, worse clinical HOA outcome was associated with coronary heart disease (OR 2.91, 95% CI (1.02 to 8.26)). The slow radiographic progression did not allow for revealing any associated factors. Conclusions: Symptomatic HOA and worse HOA clinical course are associated with coronary heart disease. These results strengthen the systemic component of HOA and the association between OA pain and cardiac events. Trial registration number: ISRCTN41323372.
INTRODUCTION Hand osteoarthritis (HOA) is a heterogeneous disorder because of its multiple risk
Key messages What is already known about this subject? ▸ Hand osteoarthritis (OA) diagnosis has been previously associated with atherosclerosis or cardiac events.
What does this study add? ▸ In a cohort of generalised OA, coronary heart disease was associated with hand OA symptoms but also worse clinical outcome, after a mean follow-up of 2.6 years.
How might this impact on clinical practice? ▸ This study strengthens the association between hand OA and cardiovascular diseases and supports that evaluating cardiometabolic comorbidities in OA participants may be useful.
factors such as inheritance, ageing, gender and obesity.1–3 In addition, HOA has been associated, although not always, with metabolic disorders (ie, diabetes, hypertension or dyslipidaemia), delineating the metabolic OA phenotype.4 5 Furthermore, cardiovascular disease (CVD) and mortality are more frequent in people with OA than without OA.6–9 A recent meta-analysis reported higher risk of CVD, especially heart failure and ischaemic heart disease, with OA than without OA but with a high heterogeneity in the design of the studies included.9 The relationship between CVD and OA has been attributed to disability, preventing people from exercising, therefore with increased cardiovascular risk. However, some studies have suggested a direct relationship between CVD and osteoarthritis (OA), independent of increased body weight and physical activity, which suggests a systemic association via a common
Courties A, et al. RMD Open 2017;3:e000344. doi:10.1136/rmdopen-2016-000344
1
RMD Open low-grade inflammation state. Indeed, HOA, which does not affect physical activity, has been independently associated with atherosclerosis or cardiac events.10 11 However, most of these studies compared CVD and metabolic disease outcomes between patients with and without HOA but did not evaluate their association with HOA symptoms or severity, which may be more representative of systemic inflammation. To better understand the association between metabolic diseases, CVD and OA, we investigated an association of cardiometabolic diseases with symptomatic HOA, radiographic severity and/or progression of HOA in a post hoc study of data from the Strontium ranelate Efficacy in Knee OsteoarthrItis triAl (SEKOIA; ISRCTN41323372), which carefully assessed HOA. PATIENTS AND METHODS Study design and patient population of SEKOIA SEKOIA is a randomised phase III, multicentre, placebocontrolled study evaluating the structural effect of strontium ranelate in knee OA. The design of this study has been previously described.12 Briefly, 1683 Caucasian patients ≥50 years old with symptomatic and primary knee OA fulfilling the American College of Rheumatology criteria with Kellgren-Lawrence (KL) knee grade 2 or 3 and minimum joint space 2.5–5 mm were randomised between April 2006 and March 2008. There were three treatment groups: strontium ranelate 1 g/day, strontium ranelate 2 g/day and placebo. The randomisation was stratified on centre and gender. Analgesics and non-steroidal anti-inflammatory drugs were permitted if stopped at least five half-lives before each visit to allow for proper symptom assessment. Patients were followed annually for 3 years, with the last visit on February 2011. The results of the main study have been previously reported.13 The study conformed to the principles of the Declaration of Helsinki; it was approved by the Ethics Committee or Institutional Review Board of every site. All patients provided written informed consent before randomisation. The trial is registered (ISRCTN41323372). Population of the ancillary study All patients with radiographic HOA (rHOA) defined as a KL score ≥2 for at least two joints at baseline were included in the cross-sectional analysis. For the longitudinal analysis, to avoid any treatment bias, we excluded patients from the treatment group and included only patients with rHOA from the placebo group at baseline. HOA evaluation For this post hoc ancillary study, bilateral anteroposterior hand radiographs taken at baseline and at the end of follow-up were scored with blinding to treatment group and in chronological order. Two expert readers 2
(EM and CC) scored half of the radiographs each, independently, by using the KL hand score (grade 0–4) for the following joints: proximal interphalangeals (PIPs 2–5), first interphalangeal (IP-1), distal interphalangeals (DIPs 2–5), metacarpophalangeals (MCPs 1–5), first carpometacarpal and scaphotrapezial. The KL hand score ranged from 0 to 128 (128 being the worst).14 Presence of erosive joints was determined by using the phase E (erosive phase) or R (remodelling phase) of the Verbruggen anatomical scoring system to analyse PIPs 2–5, IP-1, DIPs 2–5 and MCPs 1–5.15 Intrareader and inter-reader reproducibility were excellent, with intraclass correlation coefficient >0.8 for inter-reader reproducibility and >0.9 for intrareader reproducibility. Clinical evaluation of pain and disability due to HOA was assessed by the AUStralian/CANadian (AUSCAN) pain score,16 stiffness and function scores and total AUSCAN score as well as the Functional Index for HOA (FIHOA).17 For the AUSCAN, each of the three subscale scores was corrected to 100, for a range from 0 to 300 for the total score. Presence of pain was assessed by the question ‘Did you have pain in your hands during the past 48 hours?’, with a binary answer (yes/no). Definition of symptomatic HOA and clinical progression In the cross-sectional analysis, symptomatic HOA was defined by a FIHOA score ≥5 and hand pain in the past 48 hours (FIHOA≥5+presence of HOA pain). The FIHOA≥5 threshold was used because it discriminates between symptomatic and non-symptomatic HOA.18 In the longitudinal analysis, clinical progression was defined by deterioration in FIHOA score between baseline and the end of follow-up (FIHOA final minus FIHOA initial >0). The secondary clinical outcomes were AUSCAN pain score, used as a continuous variable, to determine baseline clinical symptom intensity and AUSCAN pain deterioration for clinical symptom changes. Definition of radiographic severity and radiographic progression We defined radiographic severity by using the KL hand score as a continuous variable. Radiographic progression was defined by a change in KL total score over each reader’s smallest detectable difference (SDD). The secondary structural radiographic outcomes were presence of at least one erosive joint on both hands based on the Verbruggen score ( phase E or R) and the occurrence of a new erosive joint in the cross-sectional and longitudinal analysis, respectively. Collected clinical data At baseline, the following demographic variables were collected from medical files, self-reported data and patient medications by SEKOIA study investigators without information on delay between the disease and the randomisation: age, gender, body mass index (BMI), Courties A, et al. RMD Open 2017;3:e000344. doi:10.1136/rmdopen-2016-000344
Osteoarthritis menopause status, alcohol consumption and tobacco use and comorbidities such as diabetes mellitus, hypertension, dyslipidaemia, depression, coronary heart disease (defined as acute myocardial infarction, angina pectoris, arteriosclerosis coronary artery, coronary artery disease/insufficiency/occlusion/stenosis/thrombosis, coronary heart disease, myocardial infarction and myocardial ischaemia), stroke and lower limb arteritis. Obesity was defined as BMI≥30 kg/m2. Statistical analysis Data were analysed by using SAS V.9.3 (SAS Institute, Cary, North Carolina, USA). Continuous variables are described as mean±SD or median (quartile 1–3) and categorical variables as frequencies and percentages. Comparison of cross-sectional and longitudinal data involved Fisher’s exact and Wilcoxon tests. In the crosssectional analysis, we used unadjusted logistic regression to analyse the following factors associated with symptomatic HOA (FIHOA score ≥5+pain): age, sex, menopause, obesity, history of diabetes, hypertension, dyslipidaemia, coronary heart disease (as described previously), depression, stroke, alcohol consumption, tobacco use, and rHOA and knee OA features. Linear regression was used to assess associations with AUSCAN pain and KL hand score, and logistic regression was used to assess an association with presence of at least one erosive joint. All factors associated on univariate analysis at p
